The overall Genetic Animal Models Core (GAMC) will be overseen by Dr. John Crabbe, Professor of Behavioral Neuroscience, Oregon Health Sciences University (OHSU). The major goal of the GAMC is to integrate animal model development, availability and usage across sites. It will facilitate the development of more robust phenotypes and genotypes; facilitate the exploration of gene by environment interactions and facilitate development of novel genetic technology to explore the two-hit hypothesis, i.e. that at least two clusters of genes must be dysregulated to produce abusive self-administration; to achieve coordinated genetic animal model utilization and development across INIA sites and Cores: and to provide relevant data to the Informatics Core. The Scripps Research Institute Animal Models Core Component will be primarily focused on developing more robust phenotypes and genotypes of excessive ethanol consumption. For example, a model of excessive ethanol drinking in dependent mice following periods of protracted abstinence will be developed and optimized. Mice will be trained to self-administer ethanol in an operant procedure, made dependent using an ethanol liquid diet and then allowed access to ethanol self-administration again following period of protracted abstinence. It is hypothesized that subacute withdrawal syndrome persists for weeks to months in rodents (years in humans) and may be associated with excessive or uncontrolled ethanol drinking behavior. IN addition, several mouse models available through Scripps Research Institute collaborations will be maintained and investigated in terms of ethanol self-administration in both non-dependent and dependent states. These include the corticotropin releasing factor (CRF) receptor 1 (R1) and receptor 2 (R2) knockout mice and the mu and delta opioid receptor knockout mice. These strains will be made available on a pure C57BL/6 background. Site specific mu and delta opioid receptor knockout mice with mutations targeted to extended amygdala circuitry will also become available (Kieffer, developmental U01). In addition, several mouse lines conditionally over expressing transcription factors will be investigators within this Core Component. Once characterized, these strains will become available throughout INIA for molecular, cellular and circuitry analyses.